Increased bone strength and reduced fracture risk are highly desirable outcomes in osteoporosis-related research. The most efficient way to improve bone strength is to augment bone size by targeting periosteal bone surfaces. Enhancing periosteal bone formation increases bone size, and yields greater increases in bone strength than equivalent changes in bone mass alone. Despite its widely recognized potential in augmenting bone size and strength, the regulation of periosteal bone apposition at the cellular and molecular level remain unknown. This grant focuses on the role of a novel protein called periostin, an extracellular matrix protein that is preferentially expressed on periosteal bone surfaces. Periostin exhibits unique properties that suggest it could function as a regulatory factor for anabolic actions targeting periosteal bone surfaces. The major research objective of this K01 application is to determine the role of periostin in regulating periosteal tissue- and cell-level responses to anabolic treatments (mechanical stimulation and parathyroid hormone [PTH]) and to fracture using a genetically engineered mouse model deficient in periostin, and an osteoblast reporter mouse (Col3.6-GFP) that expresses green fluorescent protein in immature osteoblasts. The principal investigator will accomplish the following specific aims: 1) determine the response of periostin null and wild-type mice to in vivo mechanical loading and PTH treatment; 2) determine the role of periostin in modulating osteoblast differentiation in vivo, using mechanical loading and PTH treatment; 3) determine the regulation of periostin using primary calvarial osteoblasts harvested from periostin null and wild-type mice challenged with fluid shear stress and PTH, and; 4) determine the fracture healing response in periostin null and wild-type mice subject to experimentally-induced long-bone fractures. In addition to addressing the aformentioned research aims, this proposal outlines a comprehensive series of research training and didactic activities which are concentrated on improving the applicant's cellular and molecular background to enable her to become an independent research scientist. LAY SUMMARY: Osteoporotic fractures are a serious public health problem. One way to prevent fractures is to improve bone strength by increasing bone size. This proposal will investigate a novel molecular pathway that may be important in influencing bone size.